This Program Project proposes to facilitate an improved understanding of biological systems governing food intake, body fat mass and obesity pathogenesis. While many key molecules and neuronal cell types have been identified, it is the interactions between them, and the impact of environmental factors on these interactions, that ultimately determine the level of body fat that is defended. Identifying these interactions, and distinguishing those that are critical from those that are not, provides the overarching focus of this proposal. Because of the complexity inherent in this undertaking, this goal is best met by uniting investigators with complementary expertise and resources in an effective and productive collaboration using a multidisciplinary approach and state-of-the-art technology. Our proposal brings Dr. Greg Barsh from Stanford University School of Medicine together with established, NIH-funded investigators at the University of Washington--Drs. Michael W. Schwartz, David E. Cummings and Denis G. Baskin--in three highly-interrelated Projects that will clarify how insulin, leptin and ghrelin interact with nutrient-related signals to regulate both feeding behavior and the function of key neuronal subsets in the hypothalamic arcuate nucleus. The success of each project will depend upon interactions between them and on support provided by a Histochemistry Core and an Animal Physiology Core. Day-to-day oversight of the entire Program Project will be provided by an Administrative Core. In the event of its funding, Dr. Paul Ramsey, Dean of the University of Washington School of Medicine, has made a major commitment of new laboratory space to support the success of this endeavor. Progress in understanding signaling networks in energy homeostasis requires an interactive, multidisciplinary research program and is critical for ongoing efforts to develop more effective strategies for obesity treatment.